Pathophysiology of Pure Autonomic Failure and Idiopathic Autonomic Neuropathy The primary hypothesis is that pure autonomic failure (PAF) and idiopathic autonomic neuropathy (IAN), two disabling and together, relatively common disorders, are different clinically, pathogenetically and pathophysiologically. We posit that PAF is a progressive selective postganglionic autonomic neuropathy, whereas IAN is a monophasic immune-mediated multifocal small fiber neuropathy, affecting both somatic and autonomic fibers. The two disorders are often confused. We will undertake a prospective study to develop a predictive prognostic model of PAF and IAN to evaluate their differentiation, course and outcome. It will be possible to generate insights into the pathophysiologies of IAN and PAF with the availability of the ganglionic antibody (positive in IAN selectively), a validated instrument to evaluate the severity and distribution of autonomic symptoms, new techniques to undertake laboratory evaluation of the systemic, splanchnic-mesenteric and cerebrovascular vasoregulation and the ability to measure muscle sympathetic nerve activity directly using microneurography. Dr. Sandroni will acquire the necessary training to undertake microneurographic, superior mesenteric blood flow, and cerebral blood flow recordings and apply them to autonomic studies on IAN and PAF. It is also possible to study the sympathetic supply to eccrine sweat gland and unmyelinated somatic fiber innervation of the skin (positive in IAN, negative in PAF) using punch skin biopsies. She will acquire training in morphometry of skin innervation, labeled with tile panaxonal marker PGP 9.5 and antibodies to tyrosine hydroxylase (autonomic fibers) and sensory neuropeptidic fibers (calcitonin gene-related peptide, substance P, vasoactive intestinal polypeptide). Finally, she will undertake a double-blind, randomized, 4-way crossover study of pyridostigmine in the treatment of neurogenic orthostatic hypotension of PAF and IAN. This strategy of acetylcholinesterase inhibition to improve ganglionic transmission could improve orthostatic hypotension without complicating supine hypertension. This research is set up to create a balance in research and clinical responsibility. The planned training in autonomic techniques and specific pathophysiologic studies will provide Dr. Sandroni with the necessary conceptual development, publications track record and investigational tools to effectively compete as an independent investigator in autonomic disorders in future years.